Hepatic encephalopathy (HE) refers to a spectrum of neurologic signs and symptoms believed to result from increased blood ammonia levels, which frequently occur in subjects with cirrhosis or certain other types of liver disease. Subjects with HE typically show altered mental status ranging from subtle changes to coma, features similar to those in subjects with urea cycle disorders (UCDs).
Glycerol phenylbutyrate (glyceryl tri-[4-phenylbutyrate]) (HPN-100, GPB, GT4P, glycerol PBA), which is described in U.S. Pat. No. 5,968,979, is currently under development for treatment of HE. Like sodium PBA (NaPBA, approved in the United States as BUPHENYL® and in Europe as AMMONAPS®) and sodium benzoate, HPN-100 is a nitrogen scavenging agent. These drugs are often referred to as alternate pathway drugs because they provide the body with an alternate pathway to urea for excretion of waste nitrogen (Brusilow 1980; Brusilow 1991).
NaPBA is a phenylacetic acid (PAA) prodrug, while HPN-100 is a prodrug of PBA and a pre-prodrug of PAA. HPN-100 and NaPBA share the same general mechanism of action: PBA is converted to PAA via beta oxidation, and PAA is conjugated enzymatically with glutamine to form phenylacetylglutamine (PAGN), which is excreted in the urine. The structures of PBA, PAA, and PAGN are set forth below.

The clinical benefit of NaPBA and HPN-100 with regard to nitrogen retention disorders such as HE derives from the ability of PAGN to effectively replace urea as a vehicle for waste nitrogen excretion and/or to reduce the need for urea synthesis (Brusilow 1991; Brusilow 1993). Because each glutamine contains two molecules of nitrogen, the body rids itself of two waste nitrogen atoms for every molecule of PAGN excreted in the urine (FIG. 1). Therefore, two equivalents of nitrogen are removed for each mole of PAA converted to PAGN. PAGN represents the predominant terminal metabolite, and one that is stoichiometrically related to waste nitrogen removal, a measure of efficacy in the case of nitrogen retention states. The difference between HPN-100 and NaPBA with respect to metabolism is that HPN-100 is a triglyceride and requires digestion, presumably by pancreatic lipases, to release PBA (McGuire 2010).
In contrast to NaPBA or HPN-100, sodium benzoate acts when benzoic acid is combined enzymatically with glycine to form hippuric acid. For each molecule of hippuric acid excreted in the urine, the body rids itself of one waste nitrogen atom.
Methods of determining an effective dosage of PAA prodrugs such as NaPBA or HPN-100 for a subject in need of treatment for a nitrogen retention disorder are described in WO09/1134460 and WO10/025303. While ammonia has long been suspected as important in the pathogenesis of HE, the data are largely correlative and it is only recently that an ammonia selective intervention has been shown to reduce the likelihood of HE events (Rockey 2012). Ammonia is not routinely monitored in patients with HE; rather, treatment is based on clinical assessment.